Update on the randomized trial of post-transplanation cyclophosphamide and rabbit ATG for graft-versus-host disease prophylaxis in chronic myeloproliferative neoplasms and myelodysplastic syndrome
Contact: Dr.Ivan S.Moiseev
Accepted 29 September 2016
Our group have previously demonstrated superiority of graftversus-host disease prophylaxis (GVHD) with post-transplanation cyclophosphamide (PTCy) over horse anti-thymocyte globulin (ATG) in acute leukemia patients undergoing unrelated hematopoietic stem cell transplantation (HSCT)1. Nevertheless, in chronic myeloproliferative neoplasms (CMN) and myelodysplastic syndrome (MDS) there is a concern of increased graft failure after PTCy. Therefore, we have initiated the single center prospective randomized trial comparing PTCy and rabbit ATG in this group of patients.
Patients and methods
The inclusion criteria were as follows: patients with CMN and MDS, unrelated HSCT, only 10/10-HLA matched patients, peripheral blood stem cells as graft source, no severe organ dysfunction. All patients received conditioning with oral busulfan 10 mg/kg and fludarabine 180 mg/m2, and GVHD prophylaxis with tacrolimus adjusted for 5-15 ng/ml concentration and 30 days of 30 mg/kg mycophenolate mofetil. The third GVHD prophylaxis agent was either PTCy 50 mg/kg day+3, +4, or rabbit ATG (Thymoglobulin) 5 mg/kg. The strata for randomization was Seattle pre-transplant assessment of mortality (PAM) index2. The primary endpoint was incidence of graft failure and secondary endpoints were GVHD and survival. The trial was registered on clinicaltrials.gov, NCT02627573. So far, 17 patients were enrolled, 9 with MDS, and 8 with MPN.
Nine patients were randomized in PTCy group and 8 in the ATG group. Median follow-up was 10 months (range 2-19). The incidence of primary and secondary graft failure was 0% vs 42%(3) in the PTCy and ATG groups (p=0.023), but the engraftment was slower in the PTCy group (20 days vs 15 days, p=0.009). Acute GVHD grade II developed in one PTCy patient and none in the ATG group, acute GVHD grade III-IV was not observed. None of patients developed moderate and severe chronic GVHD. Only 1 patient in PTCy group developed mild chronic GVHD (p=0.44). One patient in each of the groups relapsed (p=0.79). Overall survival was 100% vs 38% (p=0.002) in PTCy and ATG groups, respectively.
Despite significantly higher incidence of graft failure and lower survival in ATG group, it might be accidental, given the small group size, extremely high graft failure and lower survival than PAM-predicted in the ATG groups. The continuation of the trial is warranted. Unfortunately, the recruitment is very slow, so it may not be possible to complete the trial in the single center setting. The team is currently seeking for collaborators.
1. Moiseev IS, Pirogova OV, Alyanski AL et al. Biol Blood Marrow Transplant. 2016 Jun;22(6):1037-42.
1. Au BK, Gooley TA, Armand P et al. Biol Blood Marrow Transplant. 2015 May;21(5):848-54.
Allogeneic hematopoietic cell transplantation, cyclophosphamide, graftversus-host disease (gvhd), atg, prophylaxis